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J. Biol. Chem., Vol. 279, Issue 50, 51783-51792, December 10, 2004

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Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells^*

Gi-Ryang Kweon, Jeremy D. Marks, Robert Krencik, Eric H. Leung¶, Paul T. Schumacker||, Keith Hyland**, and Un Jung Kang¶

From the Departments of Neurology, Pediatrics, ^¶Neurobiology, Pharmacology & Physiology, and ^||Medicine, The University of Chicago, Chicago, Illinois 60637 and ^**Baylor University Medical Center, Institute of Metabolic Disease, Dallas, Texas 75226

Chronic mitochondrial dysfunction, in particular of complex I, has been strongly implicated in the dopaminergic neurodegeneration in Parkinson's disease. To elucidate the mechanisms of chronic complex I disruption-induced neurodegeneration, we induced differentiation of immortalized midbrain dopaminergic (MN9D) and non-dopaminergic (MN9X) neuronal cells, to maintain them in culture without significant cell proliferation and compared their survivals following chronic exposure to nanomolar rotenone, an irreversible complex I inhibitor. Rotenone killed more dopaminergic MN9D cells than non-dopaminergic MN9X cells. Oxidative stress played an important role in rotenone-induced neurodegeneration of MN9X cells, but not MN9D cells: rotenone oxidatively modified proteins more in MN9X cells than in MN9D cells and antioxidants decreased rotenone toxicity only in MN9X cells. MN9X cells were also more sensitive to exogenous oxidants than MN9D cells. In contrast, disruption of bioenergetics played a more important role in MN9D cells: rotenone decreased mitochondrial membrane protential and ATP levels in MN9D cells more than in MN9X cells. Supplementation of cellular energy with a ketone body, D--hydroxybutyrate, decreased rotenone toxicity in MN9D cells, but not in MN9X cells. MN9D cells were also more susceptible to disruption of oxidative phosphorylation or glycolysis than MN9X cells. These findings indicate that, during chronic rotenone exposure, MN9D cells die primarily through mitochondrial energy disruption, whereas MN9X cells die primarily via oxidative stress. Thus, intrinsic properties of individual cell types play important roles in determining the predominant mechanism of complex I inhibition-induced neurodegeneration.

Received for publication, June 30, 2004 , and in revised form, October 1, 2004.

^* The work was supported by the Parkinson's Disease Foundation and National Institutes of Health Grants R01 NS43286 (to U. J. K.), NS32080 (to U. J. K.), NS38547 (to J. D. M.), HL66315 (to P. T. S.), and T32 GM07281 (to E. H. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Neurology, MC2030, University of Chicago, Chicago, IL 60637. Tel.: 773-702-6389; Fax: 773-702-9076; E-mail: unkang{at}uchicago.edu.

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